The genetic basis for regulating the concentration of enzymes and other proteins is well established for microbial systems. On the other hand, an understanding of the fundamental mechanisms for regulating the tissue concentration of an enzyme in higher organisms is still quite limited. This project is designed to study regulatory mechanisms in higher organisms using a system in which genetics can be used to manipulate the biochemistry of mammalian tissues both during development and in the differentiated state. The enzymes and proteins to be studied include delta-aminolevulinate dehydratase, aldolase, other glycolytic enzymes and plasma membrane proteins in tissues of inbred mouse strains and other animals and tissue culture cells. Mutant genes, which affect the tissue activity of these proteins, are being identified. Among the specific questions being asked are the following: (1) Do these genes affect the primary structure or the tissue concentration of proteins? (2) What is the biochemical mechanism by which these genes exert their effect? (3) Do enzymes and membrane proteins in developing liver and hepatomas differ from enzymes in differentiated cells? (4) What is the nature of the genetic regulation during development of the liver? (5) Can other mutant genes be found which also affect these enzyme and membrane protein systems? It is anticipated that a system of mutations affecting both structural genes and genes that regulate the concentration of specific proteins will provide a valuable tool to aid in the understanding of regulatory mechanisms in animal cells.